252574-02-0Relevant articles and documents
Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4)
Brnardic, Edward J.,Ye, Guosen,Brooks, Carl,Donatelli, Carla,Barton, Linda,McAtee, Jeff,Sanchez, Robert M.,Shu, Arthur,Erhard, Karl,Terrell, Lamont,Graczyk-Millbrandt, Grazyna,He, Yanan,Costell, Melissa H.,Behm, David J.,Roethke, Theresa,Stoy, Patrick,Holt, Dennis A.,Lawhorn, Brian G.
, p. 9738 - 9755 (2018/10/31)
A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure-activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.
NON-FUSED TRICYCLIC COMPOUNDS
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Paragraph 00695, (2018/11/26)
Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
Synthesis of diversely functionalised 2,2-disubstituted oxetanes: Fragment motifs in new chemical space
Davis, Owen A.,Croft, Rosemary A.,Bull, James A.
supporting information, p. 15446 - 15449 (2015/10/20)
Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O-H insertion and C-C bond forming cyclisation.
COMPOUNDS AND METHODS FOR ANTIVIRAL TREATMENT
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Paragraph 0614-0616, (2013/10/22)
Compounds and pharmaceutically acceptable salts and esters and compositions thereof, for treating viral infections are provided. The compounds and compositions are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections
SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF USE
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, (2013/09/26)
The present invention provides novel substituted cyclic compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
STABLE SNS-595 COMPOSITIONS AND METHODS OF PREPARATION
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Page/Page column 54; 57, (2011/04/14)
Methods of preparing substantially pure SNS-595 substance are disclosed. Also provided are compositions comprising SNS-595 substance that are substantially pure and essentially free of visible particles.
Synthesis of (±)-trans-hexahydropyrrolo[3,4-d]oxazol-2-one and its derivatives by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor
Rajesh, Tammana,Rao, Sambangi Polinaini Narayana,Suresh, Kopparthi,Madhusudhan, Gutta,Mukkanti, Kagga
, p. 1392 - 1397 (2011/03/17)
Synthetic method for the preparation of (±)-trans- hexahydropyrrolo[3,4-d]oxazol-2-one and its derivatives has been developed. By one route, an efficient preparation of these fused heterobicyclic moieties could be achieved, which are prepared by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor. These fused heterobicyclic systems could be useful to develop a series of 2-oxazolidinone analogues.
METHOD OF PREPARING (+)-1,4-DIHYDRO-7-[(3S,4S)-3METHOXY-4-(METHYLAMINO)-1-PYRROLIDINYL]-4-OXO-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID
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Page/Page column 35-36, (2010/08/04)
Methods of preparing (+)-1, 4-dihydro-7-[(3S,45)-3-methoxy-4-(methylamino)-1 - pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid are disclosed. Also provided are pharmaceutical compositions comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, and methods of treatment using such compositions.
Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase
Longshaw, Alistair I.,Adanitsch, Florian,Gutierrez, Jemy A.,Evans, Gary B.,Tyler, Peter C.,Schramm, Vern L.
experimental part, p. 6730 - 6746 (2010/12/24)
5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing "sulfur-free" analogues. Herein we describe the preparation of a series of "sulfur-free" transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano-to picomolar dissociation constants and are potentially novel bacterial anti-infective and anticancer drug candidates.
MINERALOCORTICOID RECEPTOR ANTAGONISTS AND METHODS OF USE
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Page/Page column 24-25, (2009/07/10)
The present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising a compound of Formula (I) in combination with a suitable carrier, diluent, or excipient; and methods for treating physiological disorders, particularly congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
